The need for testosterone supplementation, often caused by testosterone deficiency, is a condition that can affect both men and women. Testosterone deficiency can be accompanied by a variety of symptoms including sexual dysfunction, reduced muscle mass and muscle strength, depressed mood, and osteoporosis. Male hypogonadism and female sexual dysfunction is characterized by a deficiency of endogenous testosterone production resulting in abnormally low levels of circulating testosterone. Currently, common testosterone therapy treatment can include administration of invasive intramuscular products, topical gels, topical solution and patches, or multiple units of liquid oral dosage capsules. There are challenges and drawbacks associated with each of these therapies. For example, use of topical gels or topical solutions can result in accidental transfer of the active agent to others, such as children or partners.
Current standard therapies for males aim at restoring physiologically relevant levels of testosterone in serum. It is generally recognized that in a normal adult man of age 17 to 54 yrs, the average serum testosterone (T) a major androgenic hormone in males, is between about 300 ng/dL to about 1100 ng/dL, known as the eugonadal range. Testosterone replacement in males should in theory approximate the natural, endogenous production of the hormone. The average male produces 4-7 mg of testosterone per day in a circadian pattern, with maximal plasma levels attained in early morning and minimal levels in the evening.
Low or reduced sexual desire is a condition that impacts millions of women, particularly those over the age of 50. Testosterone (T) levels can steeply decline in women as they age or after surgical menopause. Endogenous testosterone levels in women at age 40 are one half of those of women at age 21 and endogenous testosterone levels in women after oophorectomy are 50% less than before oophorectomy. There is strong indication that supplemental testosterone therapy may be beneficial for the treatment of women with reduced sexual desire. Currently in the United States, there is no approved testosterone product available for the treatment of female sexual dysfunction and reduced sexual desire. The human female has substantially lower normal blood levels of total testosterone (10-100 ng/dL compared to males ˜300-1100 ng/dL) so it can be logically surmised that efficacious doses for women can be substantially lower (about 10-50 times) than that for men.
While oral is typically the most preferred and patient friendly route for administration, the oral delivery of testosterone as testosterone remains a huge challenge. This is due to extremely poor bioavailability requiring very high dose as well as the short serum half-life requiring frequent dosing. These problems with orally administered testosterone are primarily due to first pass metabolism. Moreover, direct, oral delivery of testosterone is also known to cause enzyme induction resulting in potential drug-drug interactions. Currently, modified testosterones, in form of methyl analogue of testosterone, and as an undecanoate ester, testosterone undecanoate (TU) are available for oral administration for patients in need of testosterone therapy. However, liver damage including cholestasis, peliosis hepatitis, nodular regenerative hyperplasia, and primary hepatic tumors has been reported with use of methyl testosterone. Testosterone undecanoate, a prodrug of testosterone, containing oral dosage forms are marketed in various countries under various trade names, e.g. Andriol®, Restandol®, Andriol Testocap® etc., each of which are liquid filled soft-gelatin capsule formulations containing about 40 mg of TU in a liquid carrier. Testosterone undecanoate is converted in vivo to pharmacologically active testosterone.
However, a huge drawback of the current state of the art oral liquid testosterone undecanoate formulations is that it has to be encapsulated in a capsule dosage form presenting it with limitations with respect to acceptable capsule sizes and related drug loading limitations due to testosterone undecanoate's poor solubility. Such limitations present challenges with respect to patient compliance, because patients typically have to take multiple capsule units in order to get a sufficient dose to provide the desired efficacy. Additionally, liquid capsule formulations tend to require more complicated and costly manufacturing processes and often require special storage and handling. Moreover, liquid lipidic compositions can present oxidative instability challenges with respect to testosterone and its derivatives. Due to testosterone undecanoate's poor solubility, the production of a solid oral dosage forms such as tablets, caplets, and particulates remains an area of continuous research and development.